Abstract

In an effort to identify the developing abnormalities preceding psychosis, Dr. Ming T. Tsuang and colleagues at Harvard expanded Meehl's concept of "schizotaxia," and examined brain structure and function in families affected by schizophrenia (SZ). Here, we systematically review genetic (familial) high-risk (HR) studies of SZ using magnetic resonance imaging (MRI), examine how findings inform models of SZ etiology, and suggest directions for future research. Neuroimaging studies of youth at HR for SZ through the age of 30 were identified through a MEDLINE (PubMed) search. There is substantial evidence of gray matter volume abnormalities in youth at HR compared to controls, with an accelerated volume reduction over time in association with symptoms and cognitive deficits. In structural neuroimaging studies, prefrontal cortex (PFC) alterations were the most consistently reported finding in HR. There was also consistent evidence of smaller hippocampal volume. In functional studies, hyperactivity of the right PFC during performance of diverse tasks with common executive demands was consistently reported. The only longitudinal fMRI study to date revealed increasing left middle temporal activity in association with the emergence of psychotic symptoms. There was preliminary evidence of cerebellar and default mode network alterations in association with symptoms. Brain abnormalities in structure, function and neurochemistry are observed in the premorbid period in youth at HR for SZ. Future research should focus on the genetic and environmental contributions to these alterations, determine how early they emerge, and determine whether they can be partially or fully remediated by innovative treatments.